Desymmetrization of N-Cbz glutarimides through N-heterocyclic carbene organocatalysis

Over the past decade, the catalysis of N-heterocyclic carbenes has achieved significant advances. In this area, aldehydes, enals, and esters, are commonly employed as starting materials through various catalytic activation modes. However, NHC-activated strategy of amide and its derivatives remains elusive. Described herein is the realization of asymmetric desymmetrization of N-Cbz glutarimides with alcohols through an imide C-N bond cleavage under NHC organocatalysis. A structurally diverse set of enantioenriched 4-amido esters is generated with acceptable yields and high enantioselectivities. This method features mild reaction conditions, excellent substrate scope, and excellent atom economy. DFT calculations have been performed to explore the detailed reaction mechanism and the origin of the enantioselectivity, which indicate that the strength of the C-H···O hydrogen bond and C–H⋯π interactions should be responsible for the stereoselectivity. The current strategy could open a door for efficient construction of (R)-Rolipram with excellent stereoselectivity.


Results
Reaction optimization. Initial attempts were performed with prochiral cyclic imide 1a or N-Bn cyclic imide 1b, and ethanol 2a, one of the simplest alcohols, in the presence of the achiral triazolium N-Mes pre-catalyst A with K 2 CO 3 as the base in DCM at room temperature. Unfortunately, no reaction occurred, probably because of the insufficient reactivity of the imide C-N bond (entries 1-2). Next, prochiral N-Cbz 1c (Cbz: an electron-withdrawing and good leaving group), was investigated under the same reaction conditions. To our delight, the desired ethyl 5-(((benzyloxy)carbonyl)amino)-5oxo-3-phenylpentanoate 3a was obtained in 75% yield.
Gratifyingly, the desired enantioenriched 3a, with much structural difference of the remote third atom from the chiral center, was obtained in 78% yield with 84% ee when the aminoindanol-derived triazolium pre-catalyst B was used. This result confirmed the feasibility of NHC-activation of the imide C-N bond and catalytic asymmetric desymmetrization of prochiral cyclic imides. Next, several bases were investigated, with the inorganic base K 2 CO 3 proving to be the best choice (entries [3][4][5][6][7][8][9][10][11][12]. Subsequent solvent screening revealed that DCM was the most effective (entries [13][14][15][16]. Lowering the temperature could improve the enantioselectivity considerably (entries [17][18][19]. The product 3a was obtained in 85% yield with 95% ee when the temperature was dropped to −30°C. Reducing the catalyst loading led to a decrease in the yield and enantioselectivity considerably (entries 20 and 21). Low enantioselectivity (9% ee) was observed when the NHC C was employed (entry 22). In the absence of the catalyst, no reaction occurred (entry 23). The absolute configuration of products 3 was determined via X-ray of 3i.
Substrate scope. With acceptable optimized conditions in hand (Table 1, entry 19), we then investigated the scope of the reaction for prochiral cyclic imide substrates by using ethanol 2a as a model substrate (Fig. 2). R 1 groups bearing substituents with a variety of electronic and steric properties on the aromatic ring were well tolerated, which resulted in the formation of the corresponding products 3b-3j in good to excellent yields (73-92%) with excellent enantioselectivities (92-95% ees). Substrates with both 1-naphthyl and 2-naphthyl groups reacted smoothly to deliver the products 3k and 3l, respectively, with excellent enantioselectivities. The 2-thienyl group is well tolerated, yielding the product 3m in 84% yield with 85% ee. Notably, alkyl groups, such as Me, n-Pr, i-Pr, t-Bu, i-Bu, and Cy, were efficient substrates for this reaction to provide the products 3n-3s with good to excellent enantioselectivities (82-95% ee values). To demonstrate the generality of this catalytic asymmetric desymmetrization, the scope of the alcohols was further investigated (Fig. 2). Besides ethanol, other alkyl alcohols, such as MeOH, i-PrOH, n-PrOH, phenethyl alcohol, 1-octanol, i-BuOH, cyclohexylmethanol, cyclopentylmethanol, cyclopropylmethanol, and benzyl alcohol worked efficiently to access the desired products 3t-3af with good to excellent enantioselectivities (80-97% ee). Pleasingly, several other functionalized groups, such as terminal alkenyl, double bond, and even NHBoc groups were well-tolerated, affording the products 3ag-3ai in good to excellent yields (76-91%) with excellent enantioselectivities (91-98% ee). The protective group on the imide moiety was investigated; when Cbz was replaced with Boc, no reaction occurred under the optimized conditions, perhaps due to the greater steric hindrance of the Boc group. To our delight, raising the temperature to 30°C afforded the N-Boc product 3ad in 72% yield with 71% ee. Notably, in addition to alcohols, H 2 O is also compatible with this transformation to form 3ak in 68% yield with 79% ee. Unfortunately, other nucleophiles, such as benzyl mercaptan, and amine, did not give satisfying outcomes under the current conditions (see SI for details). Delightingly, cyclic imides with 3,5-substituents, such  reacted smoothly to give the desired product 3al in 65% yield with 46% ee. Mild reaction conditions, excellent functional group tolerance, and broad substrate scope significantly increased the utility of this method for further synthetic transformations.
After the establishment of this catalytic desymmetrization strategy, 4,4-disubstituted glutarimides 4 was further tested (Fig. 3). A variety of 4,4-disubstituted glutarimides were investigated, and 2,3-dihydrospiro[indene-1,4'-piperidine]-2',6'diones were identified as the best skeleton to give the desired products 5a-5h in 62-80% yields with 84-94% ee values. The absolute configruation of the product 5 was detemined via X-ray of 10, which was derived from the product 6b. However, other frameworks, such as tetrahydronaphthalenyl or acyclic structures could not give the desired products when NHC B was used. Instead, decarbobenzoxylation product was observed. Then, although several reaction conditions have been profoundly investigated (For details, see Supporting Information), products 5j-5o were obtained in 55-87% yields with 9-66% ee. The obtained results indicated that NHC B has proven to be the more effective for 4-substituted glutarimides and indenyl glutarimides, and NHC C has proven to be the more effective for other 4,4disubstituted glutarimides in most cases, probably due to more  Table 1, entry 19; yields (after SiO 2 chromatography purification) were based on 1. [b] Reaction was performed at −40°C. [c] Reaction was performed at 30°C. ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-31760-z  Table 1, entry 19; yields (after SiO 2 chromatography purification) were based on 4. [b] Reaction was performed at −30°C.
[c] NHC precursor C was used. Reaction was performed at −30°C.   (1)1.90 (2)  steric hindrance of 4,4-disubstituted glutarimides. Furthermore, prochiral center far away from the reaction site and similar two substituted groups on the prochiral center led to difficulty realize considerable enantiomeric control for 4,4-disubstituted glutarimides.
Mechanistic studies. To shed light on the mechanism and origin of stereoselectivity for these efficient desymmetrizations of cyclimides in an excellent enantioselecitivity manner, we have DFT calculations by using Gaussian program 64 , and more computational details can be found in Supporting Information. As shown in Fig. 4, four steps including nucleophilic addition via transition states TS1R (14.1 kcal/mol) and TS1S (15.9 kcal/mol), which is followed by C-N bond cleavage via transition states TS2R (18.7 kcal/mol) and TS2S (20.1 kcal/mol). Subsequently, nucleophilic addition coupled with a proton transfer undergoes transition states TS3R (14.0 kcal/mol) and TS3S (17.2 kcal/mol). The final step is the dissociation of NHC with products via transition states TS4R (14.4 kcal/mol) and TS4S (15.9 kcal/mol). The R-isomer pathway locates below the S-isomer pathway in the Gibbs free energy file. Particularly, the energy of TS3R is 2.8 kcal/mol lower than that of TS3S, indicating the pathway associated with Risomer should be more energetically favorable in kinetics. This conclusion is in agreement with the experimental results.
To probe the reaction pathway, control experiment was performed as shown in Fig. 5. Treatment of 1c with 1.0 equiv. of NHC B was performed in the presence of K 2 CO 3 in DCM for 8 h. Immediately, the high-resolution mass spectroscopy (HRMS-ESI) analysis of the reaction mixture was carried out. And one signal peak was detected at m/z 655.2922. M + value combined with the isotope distribution pattern on HRMS analysis of the NHC-substrate adduct which probably corresponded to the intermediate Int-1.
To reveal the origin and determining factor of enantioselectivity, the energy decomposition has been performed by using PSI4 65,66 . The energy decomposition analysis summarized in Table S2 of SI indicates that the interim dispersion should be responsible for the favorability of R-isomer pathway via TS2R. Non-covalent interaction (NCI) and atoms-in-molecules (AIM) analyses have been performed by using Multiwfn 67 , and the results have been shown in Fig. 6. As depicted in Fig. 6 Synthetic transformations. Subsequently, further synthetic transformations of the resulting products were conducted as shown in Fig. 7. Treatment of 3c with Pd/C under 1 atm H 2 , followed by the reduction with LiAlH 4 furnished product 6 in 74% yield with 91% ee. Especially, 3i underwent decarbobenzyloxylation followed by hydrolysis to result in the formation of 7 in excellent yield, which was then converted into the skeletal muscular relaxants (R)-Baclofen 8 via a known process 73 . More importantly, (R)-Rolipram 9, which is a phosphodiesterase inhibitor with antidepressant properties 74 , was prepared in 50% overall yields with 95% ee from 3j via a stepwise sequence of decarbobenzyloxylation, decarbonylation of the amide moiety and an intramolecular lactamization. The compound 6b was smoothly converted into product 10 in 45% yield with 97% ee after recrystallization by using a similar strategy.

Discussion
In summary, we have developed an NHC-enabled desymmetrization of N-Cbz glutarimides with alcohols under mild conditions via imide C-N bond activation. A diverse set of enantioenriched 4-amido esters was obtained in good yields with good to excellent enantioselectivities. This reaction features mild reaction conditions, wide substrate scope, and an excellent atom economy. DFT calculations and NCI analysis indicate that the C-H⋯O hydrogen bond and C-H⋯π interactions between the NHC catalyst and substrate should be the key for controlling the enantioselectivity. Importantly, the resulting product was converted into (R)-Rolipram in 50% overall yields with 95% ee. In summary, this case work combined with experimental and theoretical studies should be valuable for understanding the similar organocatalytic desymmetrization reactions of cyclic imides with imide C-N bond activation. Further investigations and exploration of this catalytic process are underway in our laboratory.

Methods
General procedure for the synthesis of 3. To a suspension of starting materials 1 (0.10 mmol), catalyst B (7.3 mg, 20 mol%) and K2CO3 (0.15 mmol, 20.7 mg) in DCM (1.0 mL, 0.10 M) was added the appropriate alcohols (0.15 mmol, 1.5 equiv.). The mixture was stirred for 72 h at −30°C. Upon completion of the reaction (monitored by TLC), the reaction mixture was directly purified by column chromatography on silica gel to afford the desired product 3. The X-ray crystallographic coordinates for structures of 3i and 10 reported in this study have been deposited in the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 2115884(3i), and 2115883 (10). These data can be obtained free of charge from http://www.ccdc.cam.ac.uk/data_request/cif. The experimental procedures, characterization of the new compounds, and computational studies in this study are provided in Supplementary Information and Supplementary Data 1. All other data are available from the authors upon request.